Atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p

Zhang, Jie; Zhang, Yinzhuang; Peng, Junwen; Li, Nian-Sheng; Xiong, Xiaofang; Ma, Qin; Luo, Xiu-Ju; Liu, Bin; Peng, Jun

doi:10.1016/j.mad.2017.12.001

Cited by 15 publications

(14 citation statements)

References 20 publications

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“…Our results also confirm pleiotropic effects of statin and aspirin such as reducing stress-induced premature senescence. Similar anti-senescent effects of statins and aspirin have been previously reported in endothelial progenitor, endothelial, and vascular smooth muscle cells [32][33][34][35] . These anti-senescent effects may be linked, at least partially, to reducing oxidative stress, DNA damage, and preventing hyper-responsiveness of AT1R to AngII stimulation 36,37 .…”

Section: Discussionsupporting

confidence: 82%

Chronic Intermittent Hypoxia Triggers a Senescence-like Phenotype in Human White Preadipocytes

Polonis

Becari

Chahal

et al. 2020

Sci Rep

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Obstructive sleep apnea (OSA) is a common sleep disorder associated with obesity. Emerging evidence suggest that OSA increases the risk of cardiovascular morbidity and mortality partly via accelerating the process of cellular aging. Thus, we sought to examine the effects of intermittent hypoxia (IH), a hallmark of OSA, on senescence in human white preadipocytes. We demonstrate that chronic IH is associated with an increased generation of mitochondrial reactive oxygen species along with increased prevalence of cells with nuclear localization of γH2AX & p16. A higher prevalence of cells positive for senescence-associated β-galactosidase activity was also evident with chronic IH exposure. Intervention with aspirin, atorvastatin or renin-angiotensin system (RAS) inhibitors effectively attenuated IHmediated senescence-like phenotype. Importantly, the validity of in vitro findings was confirmed by examination of the subcutaneous abdominal adipose tissue which showed that OSA patients had a significantly higher percentage of cells with nuclear localization of γH2AX & p16 than non-OSA individuals (20.1 ± 10.8% vs. 10.3 ± 2.7%, P adjusted < 0.001). Furthermore, the frequency of dual positive γH2AX & p16 nuclei in adipose tissue of OSA patients receiving statin, aspirin, and/or RAS inhibitors was comparable to non-OSA individuals. This study identifies chronic IH as a trigger of senescence-like phenotype in preadipocytes. Together, our data suggest that OSA may be considered as a senescencerelated disorder.Obstructive sleep apnea (OSA), a sleep breathing disorder, poses a significant worldwide public health problem associated with a higher cardiovascular and metabolic risk 1 . While it is well established that exposure to repetitive intermittent hypoxia (IH) during sleep contributes to OSA pathophysiology, the mechanisms by which the acute physiological disruptions translate into long-term health consequences are not completely understood. The importance of this issue is underscored by recent studies showing that continuous positive airway pressure (CPAP) therapy has been unable to effectively reduce cardiovascular events in OSA patients 2-4 . The inability of CPAP to diminish cardiometabolic risk suggests other mechanisms which do not readily reverse by elimination of IH, and may continue to mediate OSA-related pathogenesis, even after cessation of exposure to IH.Senescence is a fundamental mechanism implicated in tissue dysfunction and aging processes, including chronic diseases such as diabetes, metabolic dysfunction and cardiovascular disease (CVD) 5-7 . In healthy tissue, senescent cells are eliminated by the immune system which drives tissue regeneration 8 ; however, stress stimuli may corrupt this process and lead to increased accumulation of senescent cells. Increased senescence may limit tissue regenerative capacity and aggravate tissue dysfunction, presumably through intracellular signaling loops including senescence-associated secretory phenotype 9 . Therefore, senescence represents a self-propagating mechanism ...

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Section: Discussionsupporting

confidence: 82%

Chronic Intermittent Hypoxia Triggers a Senescence-like Phenotype in Human White Preadipocytes

Polonis

Becari

Chahal

et al. 2020

Sci Rep

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“…The same oxidized lipids found in ox-LDL are also formed in apoptotic cells and are present in circulation and tissues under pathological conditions. Excessive lipids, particularly ox-LDL, cause endothelial dysfunction and ultimately result in multiple cardiovascular diseases [2]. Under shear stress, normal endothelium produces vasodilators, including nitric oxide (NO), to control the blood pressure in blood vessels.…”

Section: Introductionmentioning

confidence: 99%

Mulberry Extract Attenuates Endothelial Dysfunction through the Regulation of Uncoupling Endothelial Nitric Oxide Synthase in High Fat Diet Rats

et al. 2019

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Dyslipidemia is associated with endothelial dysfunction, which is linked to nitric oxide (NO) biology. The coupling of endothelial NO synthase with cofactors is a major step for NO release. This study is aimed to investigate the vascular pharmacology effects of mulberry in rat thoracic aorta and human vascular endothelial cells. In vitro, we investigated the protective effects of the mulberry extract and its main component cyanidin-3-rutinoside (C-3-R), against oxidized low-density lipoprotein (ox-LDL)-induced endothelial nitric oxide synthase (eNOS) uncoupling. Whereas ox-LDL significantly decreased NO levels in endothelial cells, mulberry extract, and C-3-R significantly recovered NO levels and phospho-eNOS Thr495 and Ser1177 expression. In vivo, mulberry was administered to 60% of high-fat diet (w/w)-fed Sprague Dawley (SD) rats for six weeks, in which endothelium-dependent relaxations were significantly improved in organ bath studies and isometric tension recordings. Consistently, aortic expressions of phospho-eNOS and nitrotyrosine were increased. Mulberry also raised serum NO levels, increased phosphorylation of eNOS, and reduced nitrotyrosine and intracellular reactive oxygen species (ROS) in aortas, showing that mulberry preserves endothelium-dependent relaxation in aortas from high-fat diet rats. We suggest that this effect is mediated through enhanced NO bioavailability, in which the regulation of ROS and its reduced eNOS uncoupling are involved.

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“…ER stress markers included the ATF4, ATF6, CHOP, and GRP78. ATF4/ATF6 [ 21 , 22 ] which activates transcription factor (ATF/CREB) family, molecular chaperone GRP78 in the endoplasmic reticulum, and CHOP, a transcription factor that mediates endoplasmic reticulum stress-induced apoptosis [ 23 ], P53 [ 5 ], etc. have an important relationship with oxidative stress and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-Glucoside modulated human umbilical vein endothelial cells injury under oxidative stress

Guo

Fan

Cao

et al. 2020

Korean J Physiol Pharmacol

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Endothelial cell injury is a major contributor to cardiovascular diseases. The 2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-Glucoside (TSG) contributes to alleviate human umbilical vein endothelial cells (HUVECs) injury through mechanisms still know a little. This study aims to clarify the TSG effects on gene expression (mRNA and microRNA) related to oxidative stress and endoplasmic reticulum stress induced by H 2 O 2 in HUVECs. We found that TSG significantly reduced the death rate of cells and increased intracellular superoxide dismutase activity. At qRT-PCR, experimental data showed that TSG significantly counteracted the expressions of miR-9-5p, miR-16, miR-21, miR-29b, miR-145-5p, and miR-204-5p. Besides, TSG prevented the expression of ATF6 and CHOP increasing. In contrast, TSG promoted the expression of E2F1. In conclusion, our results point to the obvious protective effect of TSG on HUVECs injury induced by H 2 O 2 , and the mechanism may through miR16/ATF6/ E2F1 signaling pathway.

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Atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p

Cited by 15 publications

References 20 publications

Chronic Intermittent Hypoxia Triggers a Senescence-like Phenotype in Human White Preadipocytes

Chronic Intermittent Hypoxia Triggers a Senescence-like Phenotype in Human White Preadipocytes

Mulberry Extract Attenuates Endothelial Dysfunction through the Regulation of Uncoupling Endothelial Nitric Oxide Synthase in High Fat Diet Rats

2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-Glucoside modulated human umbilical vein endothelial cells injury under oxidative stress

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